The ultimate objective of the proposed investigation is the elucidation of the mechanism(s) of genetically controlled resistance in three mouse systems. Genetically controlled resistance to flavi-virus infection, mouse hepatitis virus infection, and influenza virus infection, will be investigated. In all three systems, resistance has been demonstrated on the cellular level. SV40-transformed cell lines derived from resistant and susceptible animals will be produced and viral RNA and protein synthesis will be compared in these resistant and susceptible cell cultures. In the flavi-virus system, an involvement of defective interfering virions has been indicated. The synthesis of such particles will be investigated in all three systems. The ability of viruses to establish persistent infections in resistant cells and resistant animals will also be studied. The existing data on the involvement of components of the immune system in the phenotypic expression of genetically controlled resistance in vivo is not sufficient for any of the three systems to draw any definite conclusions. In vitro cytotoxicity assays will be used to assess immune responses to infection. Virus infection of immunosuppressed or innumodeficient resistant and susceptible animals will be compared.